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Figure 1.
Probabilistic Sensitivity Analyses Showing the Proportion of Optimal Simulations as a Function of Drug Price
Probabilistic Sensitivity Analyses Showing the Proportion of Optimal Simulations as a Function of Drug Price

At 2015 US prices and a threshold of $100 000 per quality-adjusted life-year (QALY), proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were not cost-effective among patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. Lowering the drug price or increasing the cost-effectiveness threshold would increase the proportion of simulations that are cost-effective. Vertical dotted lines show the list price of a 1-year supply of evolocumab in the United States ($14 100), the United Kingdom ($6427; the National Health Service receives an additional discount), Austria ($8110), and Finland ($8700).45,46

Figure 2.
Incremental Cost-effectiveness Ratio (ICER) of PCSK9 Inhibitor Therapy Among Patients With Heterozygous Familial Hypercholesterolemia or Atherosclerotic Cardiovascular Disease
Incremental Cost-effectiveness Ratio (ICER) of PCSK9 Inhibitor Therapy Among Patients With Heterozygous Familial Hypercholesterolemia or Atherosclerotic Cardiovascular Disease

The ICER for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy increases with the annual cost of PCSK9 inhibitor therapy. Blue, orange, and black data markers indicate the price at which PCSK9 inhibitor therapy would become cost-effective in the United States at willingness-to-pay thresholds of $150 000 per quality-adjusted life-year (QALY) ($6810), $100 000 per QALY ($4536), and $50 000 per QALY ($2261), respectively. In the base case, status quo statin plus PCSK9 inhibitor therapy is compared with status quo statin plus ezetimibe (black line). When PCSK9 inhibitor therapy costs less than $7049 per year (inflection in the graph), ezetimibe is eliminated by extended dominance and status quo statin plus PCSK9 inhibitory therapy is compared directly with status quo statin therapy (gray line). For reference, vertical lines include the list price of a 1-year supply of evolocumab in the United States and 3 European countries.

Table 1.  
Key Input Parameters in the Cardiovascular Disease Policy Model
Key Input Parameters in the Cardiovascular Disease Policy Model
Table 2.  
Baseline Clinical Characteristics and Modeled MACE Rates Among Treatment Populations Included in the Model (US Adults Aged 35-74 Years in 2015 Eligible for Additional Lipid-Lowering Therapy)
Baseline Clinical Characteristics and Modeled MACE Rates Among Treatment Populations Included in the Model (US Adults Aged 35-74 Years in 2015 Eligible for Additional Lipid-Lowering Therapy)
Table 3.  
Modeling Results: Clinical and Economic Outcomes Over the Lifetime Analytic Horizona
Modeling Results: Clinical and Economic Outcomes Over the Lifetime Analytic Horizona
Table 4.  
Effect of PCSK9 Inhibitors on Total Health Care Spending Over 5 Yearsa
Effect of PCSK9 Inhibitors on Total Health Care Spending Over 5 Yearsa
Supplement.

eAppendix. Additional Modeling Details

eTable 1. Bivariate Distribution of Statin Use and LDL-Cholesterol Level Among Individuals With a History of Coronary Heart Disease or Stroke in the CVD Policy Model (Estimated From NHANES 2005-2012)

eTable 2. Rates of Myocardial Infarction in the CVD Policy Model, Conditional on Age, Gender, and Health State

eTable 3. Model Validation: Comparisons of Selected Cardiovascular Disease Policy Model Simulation Outputs for 2010 (Model Base Year) With National Targets for 2010

eTable 4. Model Validation Against the West of Scotland Coronary Prevention Study

eTable 5. PRISMA Information Regarding Meta-analysis to Estimate Relative Risk of Major Coronary Events With PCSK9 Inhibitor Therapy

eTable 6. Reduction in Risk of a Major CHD Event Among Patients Receiving a High-Intensity Statin, Ezetimibe, or a PCSK9 Inhibitor

eTable 7. Pre-specified One-Way Sensitivity Analyses

eTable 8. Additional Input Parameters for Sensitivity Analyses

eTable 9. Model Validation: Comparison of Predicted Rates of Major Adverse Cardiovascular Events (MACE) Among the Atherosclerotic Cardiovascular Disease Population With Observed MACE Rates in Statin Trials

eTable 10. Additional Clinical and Economic Outcomes

eTable 11. Threshold Analyses

eTable 12. Additional Modeling Results: Combined Analysis of Patients With Familial Hypercholesterolemia or Atherosclerotic CV Disease

eTable 13. Scenario Analysis: Modeling Effect Sizes Observed in Clinical Trials (Rather Than the LDL Hypothesis)

eTable 14. Scenario Analysis: Modeling Quality-of-Life Estimates Derived From the Medical Expenditure Panel Survey

eTable 15. Scenario Analysis: Modeling the Effect of Stopping PCSK9 Inhibitor Therapy at Age 75 Years

eTable 16. Two-Way Sensitivity Analysis: Pill Disutility vs Injection Disutility

eTable 17. Scenario Analysis: Modeling Mild Neurocognitive Deficit as an Adverse Event Related to PCSK9 Inhibitor Therapy

eTable 18. Scenario Analysis: Modeling PCSK9 Inhibitor Therapy in Patients With Statin Intolerance

eTable 19. Scenario Analysis: Modeling a High-Risk Population of U.S. Adults Age 35-74 Years Who Experienced Their First-Ever MI in 2015

eFigure 1. Schematic of the Cardiovascular Disease Policy Model

eFigure 2. Effect of PCSK9 Inhibitor Therapy on Major Coronary Events

eFigure 3. One-Way Sensitivity Analyses

eFigure 4. Probabilistic Sensitivity Analyses

eFigure 5. Net Monetary Benefit

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Original Investigation
August 16, 2016

Cost-effectiveness of PCSK9 Inhibitor Therapy in Patients With Heterozygous Familial Hypercholesterolemia or Atherosclerotic Cardiovascular Disease

Author Affiliations
  • 1Department of Medicine, Center for Vulnerable Populations, University of California, San Francisco
  • 2Department of Medicine, University of California, San Francisco
  • 3Department of Epidemiology and Biostatistics, University of California, San Francisco
  • 4Center for Healthcare Value, University of California, San Francisco
  • 5Division of Cardiology, Zuckerberg San Francisco General Hospital, San Francisco, California
  • 6Division of General Internal Medicine, Columbia University Medical Center, New York, New York
  • 7College of Physicians and Surgeons, Columbia University, New York, New York
  • 8Division of General Internal Medicine, Zuckerberg San Francisco General Hospital, San Francisco, California
  • 9Institute for Clinical and Economic Review, Boston, Massachusetts
JAMA. 2016;316(7):743-753. doi:10.1001/jama.2016.11004
Abstract

Importance  Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were recently approved for lowering low-density lipoprotein cholesterol in heterozygous familial hypercholesterolemia (FH) or atherosclerotic cardiovascular disease (ASCVD) and have potential for broad ASCVD prevention. Their long-term cost-effectiveness and effect on total health care spending are uncertain.

Objective  To estimate the cost-effectiveness of PCSK9 inhibitors and their potential effect on US health care spending.

Design, Setting, and Participants  The Cardiovascular Disease Policy Model, a simulation model of US adults aged 35 to 94 years, was used to evaluate cost-effectiveness of PCSK9 inhibitors or ezetimibe in heterozygous FH or ASCVD. The model incorporated 2015 annual PCSK9 inhibitor costs of $14 350 (based on mean wholesale acquisition costs of evolocumab and alirocumab); adopted a health-system perspective, lifetime horizon; and included probabilistic sensitivity analyses to explore uncertainty.

Exposures  Statin therapy compared with addition of ezetimibe or PCSK9 inhibitors.

Main Outcomes and Measures  Lifetime major adverse cardiovascular events (MACE: cardiovascular death, nonfatal myocardial infarction, or stroke), incremental cost per quality-adjusted life-year (QALY), and total effect on US health care spending over 5 years.

Results  Adding PCSK9 inhibitors to statins in heterozygous FH was estimated to prevent 316 300 MACE at a cost of $503 000 per QALY gained compared with adding ezetimibe to statins (80% uncertainty interval [UI], $493 000-$1 737 000). In ASCVD, adding PCSK9 inhibitors to statins was estimated to prevent 4.3 million MACE compared with adding ezetimibe at $414 000 per QALY (80% UI, $277 000-$1 539 000). Reducing annual drug costs to $4536 per patient or less would be needed for PCSK9 inhibitors to be cost-effective at less than $100 000 per QALY. At 2015 prices, PCSK9 inhibitor use in all eligible patients was estimated to reduce cardiovascular care costs by $29 billion over 5 years, but drug costs increased by an estimated $592 billion (a 38% increase over 2015 prescription drug expenditures). In contrast, initiating statins in these high-risk populations in all statin-tolerant individuals who are not currently using statins was estimated to save $12 billion.

Conclusions and Relevance  Assuming 2015 prices, PCSK9 inhibitor use in patients with heterozygous FH or ASCVD did not meet generally acceptable incremental cost-effectiveness thresholds and was estimated to increase US health care costs substantially. Reducing annual drug prices from more than $14 000 to $4536 would be necessary to meet a $100 000 per QALY threshold.

Introduction

Quiz Ref IDProprotein convertase subtilisin/kexin type 9 (PCSK9) facilitates the degradation of low-density lipoprotein (LDL) receptors, reducing the clearance of circulating LDL particles.1 PCSK9 activity is inversely related to LDL cholesterol (LDL-C) level: gain-of-function PCSK9 gene mutations are one cause of elevated LDL-C and cardiovascular risk in familial hypercholesterolemia (FH),2 whereas loss-of-function mutations cause low LDL-C and reduced risk of atherosclerotic cardiovascular disease (ASCVD).3 These observations spurred the development, testing, and US Food and Drug Administration (FDA) approval of 2 therapeutic agents that inhibit PCSK9 and lower LDL-C.1

In clinical trials of 3 to 12 months’ duration, 2 PCSK9 inhibitors, alirocumab and evolocumab, reduced mean LDL-C levels by 47.5% (95% CI, 25.3%-69.6%).4,5 Although these trials were not powered for clinical outcomes, ASCVD events appeared to be reduced with PCSK9 inhibitor treatment (odds ratio for myocardial infarction [MI], 0.49; 95% CI, 0.26-0.93).4 Based on these data, PCSK9 inhibitors were approved for use in patients with FH or preexisting ASCVD who require additional lowering of LDL-C despite maximally tolerated doses of statins.1 If clinical benefits seen in short-term trials are sustained in the longer term, PCSK9 inhibitors could become an important option for patients at high risk of ASCVD, potentially lowering health care costs through preventing ASCVD events. However, with a mean US price in 2015 of more than $14 000 per patient per year, their cost-effectiveness and effect on national health care spending are uncertain. The goal of this study was to assess the value of PCSK9 inhibitors from the health system perspective by conducting a cost-effectiveness analysis and examining potential effects on total US health care spending using an established simulation model of ASCVD in the US population.

Box Section Ref ID

Key Points

  • Question What are the cost-effectiveness and potential effect on health care spending of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor treatment in heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease?

  • Findings In this simulation model of US adults aged 35 to 94 years, adding PCSK9 inhibitor therapy to current statin regimens was estimated to cost $423 000 per quality-adjusted life-year (QALY) gained compared with adding ezetimibe and increased US health care costs by $565 billion over 5 years (including a 38% increase in annual prescription drug expenditures over 2015 levels). Price reductions from more than $14 000 annually to $4536 would be necessary to meet a $100 000 per QALY threshold.

  • Meaning Assuming 2015 prices, PCSK9 inhibitor use did not meet generally accepted cost-effectiveness thresholds and was estimated to increase US health care costs substantially.

Methods

The institutional review boards of the University of California, San Francisco, and Columbia University approved the analyses of Framingham data. All other analyses were conducted on publicly available data.

Model Structure

The Cardiovascular Disease Policy Model is an established simulation model of coronary heart disease and stroke incidence, prevalence, mortality, and costs in the US population aged 35 years or older (eFigure 1 in the Supplement).68 In the population without ASCVD, the model predicts incidence of coronary heart disease, stroke, and death due to noncardiovascular causes as a function of age, sex, and conventional ASCVD risk factors (systolic blood pressure, smoking status, diabetes mellitus, body mass index, high-density lipoprotein cholesterol, and LDL-C). In those who develop ASCVD, the model characterizes the initial event (cardiac arrest, MI, angina, or stroke) and its sequelae, including cardiovascular death, for 30 days. In the populations with a history of ASCVD, the model predicts subsequent cardiovascular events, coronary revascularization procedures, and cardiovascular or noncardiovascular mortality as a function of age, sex, and clinical history.

The model included the entire population of US adults aged 35 to 74 years in 2015 and followed them over their lifetime (until death or survival to 95 years of age). The prevalence of cardiovascular risk factors was estimated from population-weighted National Health and Nutrition Examination Surveys (NHANES) from 2005-2012.9 Utilities and costs were assigned to each clinical event and health state in annual cycles and discounted at 3% annually10 (Table 1). The model assumed the health system perspective, considering all direct health care costs (including immediate and downstream costs associated with disease progression or longer life expectancy). Extensive deterministic and probabilistic sensitivity analyses were conducted to account for input parameter uncertainty. The model adhered to recommendations of the Panel on Cost-Effectiveness in Health and Medicine.10 Additional modeling details, including estimation of input parameters and calibration of the model, are in eFigures 1 and 2 and eTables 1 through 9 in the Supplement.

Target Population

Base-case simulations modeled the cost-effectiveness of PCSK9 inhibitors in 2 target adult populations defined using NHANES to approximate current FDA-approved indications38,39:

  • Heterozygous FH: either (1) family history of premature coronary heart disease and LDL-C level of at least 190 mg/dL (4.91 mmol/L) without statin therapy or LDL-C level of at least 150 mg/dL (3.88 mmol/L) with statin therapy (in line with the recent consensus statement of the American Heart Association)40,41 or (2) no family history of premature coronary disease and LDL-C level of at least 250 mg/dL (6.46 mmol/L) without statin therapy or LDL-C level of at least 200 mg/dL (5.17 mmol/L) with statin therapy

  • Preexisting ASCVD: history of angina, MI, or stroke, with LDL-C level of at least 70 mg/dL (1.81 mmol/L) despite maximally tolerated statin therapy

The base-case assumption was that 10% of each population was “statin intolerant,” but the size of this population varied in sensitivity analyses.42,43

Treatment Strategies

Three treatment strategies were modeled: (1) status quo, defined by statin use as identified in the 2005-2012 NHANES; (2) incremental treatment with ezetimibe; and (3) incremental treatment with PCSK9 inhibitors. In each case, the incremental drug was added to statin therapy or was used as monotherapy among those intolerant to statins.

The degree of LDL-C reduction with ezetimibe and PCSK9 inhibitors was estimated from the published literature (Table 1). Statins, ezetimibe, and PCSK9 inhibitors were each assumed to reduce the risk of cardiovascular events by an identical amount per milligram per deciliter of LDL-C reduction.13,14 Alternative assumptions were modeled in sensitivity analyses.

Among patients receiving PCSK9 inhibitor therapy, 5% were assumed to develop mild injection site reactions resulting in a small disutility, without an increase in costs or treatment discontinuation.15,17,18,21,24

Costs and Utilities

Age- and sex-specific health care costs were estimated using national data (Table 1).2731 Annual drug costs were assumed to be equal to their wholesale acquisition costs26; in the case of PCSK9 inhibitors, this was assumed to be the mean of the 2015 annual costs of alirocumab ($14 600) and evolocumab ($14 100).26,44 Health-related quality-of-life weights and severity distributions for ASCVD states were based on the Global Burden of Disease 2010 study.3234

Main Outcomes and Measures

The primary outcome was the incremental cost-effectiveness ratio (ICER; cost per quality-adjusted life-year [QALY]) over the lifetime analytic horizon.10 Secondary outcomes were (1) incremental cost per life-year gained; (2) the number of patients that would need to be treated for 5 years to avert 1 major adverse cardiovascular event (MACE, defined as a composite of cardiovascular death, nonfatal MI, or nonfatal stroke); (3) the price at which the drugs became cost-effective at a willingness-to-pay threshold of $100 000 per QALY; (4) the total effect on the US health care budget over the next 5 years if all eligible patients were to receive PCSK9 inhibitors (compared with receipt of ezetimibe); and (5) the net monetary benefit of incremental therapy with a PCSK9 inhibitor at willingness-to-pay thresholds ranging from $50 000 to $1 000 000 per additional QALY.

Sensitivity Analyses

One-way sensitivity analyses for key input parameters were performed by varying one input at a time while holding others constant at their base-case estimates. Several prespecified scenario analyses were also performed, including (1) using higher LDL-C thresholds to define heterozygous FH (LDL-C ≥250 mg/dL [6.46 mmol/L] without statin therapy or LDL-C ≥200 mg/dL [5.17 mmol/L] with statin therapy) and assuming a higher ASCVD risk than predicted by LDL-C level (2 times the risk for individuals with heterozygous FH compared with individuals without FH for the same LDL-C level); (2) modeling the main effect of ezetimibe and PCSK9 inhibitors on cardiovascular outcomes as seen in clinical trials (rather than based on the LDL-C hypothesis; eTable 6 in the Supplement)1423; (3) initiating PCSK9 inhibitors only after incident MI (by simulating addition of PCSK9 inhibitors among those with incident MI in the base year); (4) initiating PCSK9 inhibitor monotherapy among all patients with heterozygous FH or ASCVD requiring additional lipid lowering and not currently taking a statin or unable to tolerate statins; (5) varying the prevalence of statin intolerance between 3% and 20%; (6) modeling a 0.5% incidence of mild neurocognitive defects in patients receiving PCSK9 inhibitor therapy; and (7) treating all currently untreated, statin-tolerant individuals with statins.

Probabilistic sensitivity analyses simultaneously varied multiple input parameters across prespecified statistical distributions in 1000 iterations. Table 1 shows the range and type of distribution used for each input parameter. The results of these simulations captured the uncertainty in key outcomes and are presented as (1) 80% uncertainty intervals (UIs) around the point estimate for clinical and economic outcomes and (2) acceptability curves showing the proportion of simulations in which PCSK9 inhibitor therapy was the optimal treatment strategy at various willingness-to-pay thresholds. Of note, 80% (rather than 95%) UIs were chosen to avoid issues related to extreme outliers such as flipped ordering of strategies or negative ICERs. See the eAppendix in the Supplement for additional methodologic details.

The CVD Policy Model is programmed in Lahey Fortran 95. Modeled outcomes were analyzed using QuickBasic64 and Excel 2011 (Microsoft) and statistical analyses were performed using SAS version 9.4 (SAS Institute Inc) and Stata version 13 (StataCorp).

Results
Base-Case Analysis

Of 1.7 million individuals aged 35 to 74 years who met criteria for heterozygous FH, 1.1 million (61%) were either taking a statin or designated as statin intolerant and thus eligible for ezetimibe or PCSK9 inhibitor treatment (Table 2). Mean age was 51 years and mean LDL-C level was 207 mg/dL (5.36 mmol/L). Addition of ezetimibe to statin therapy was estimated to avert 214 400 MACE and generate 475 100 additional QALYs at an ICER of $152 000 per QALY (Table 3 and eTable 10 in the Supplement). Compared with adding ezetimibe, adding a PCSK9 inhibitor was estimated to result in 316 300 fewer MACE and 628 500 additional QALYs. The number needed to treat over 5 years to prevent 1 MACE in patients with heterozygous FH currently taking statins or statin intolerant was estimated to be 72 for ezetimibe relative to status quo and 59 for PCSK9 inhibitors relative to ezetimibe. Treating the entire 35- to 74-year-old FH population taking statins or statin intolerant with PCSK9 inhibitors over their lifetime was estimated to cost $323 billion more than treating with ezetimibe; an estimated $17 billion would be offset by decreased cost of cardiovascular care due to averted events, leading to a net of $582 000 per life-year gained or $503 000 per QALY (Table 3).

Among the 13.0 million individuals with ASCVD, 8.5 million (65%) either were taking a statin with an LDL-C level higher than 70 mg/dL or were statin intolerant; mean age was 61 years and mean LDL-C level was 109 mg/dL (2.82 mmol/L) (Table 2). Addition of ezetimibe to statin therapy was estimated to avert 2.7 million MACE and generate 5.3 million QALYs at an ICER of $154 000 per QALY (Table 4 and eTable 10 in the Supplement). In contrast, addition of a PCSK9 inhibitor to statin therapy was estimated to avert an additional 4.3 million MACE and produce 7.9 million additional QALYs (compared with ezetimibe plus statin). The number needed to treat over 5 years to prevent 1 MACE among those with ASCVD and not meeting the LDL-C goal despite maximally tolerated statin therapy was estimated to be 51 for ezetimibe compared with status quo and 35 for PCSK9 inhibitors relative to ezetimibe. PCSK9 inhibitor therapy over the lifetime in this population was projected by the model to cost $3.3 trillion more than treating with ezetimibe, but $155 billion was estimated to be offset by decreased cost of cardiovascular care due to averted events, for a net of $378 000 per life-year gained or $414 000 per QALY (Table 3).

One-Way and Probabilistic Sensitivity Analyses

In 1-way sensitivity analyses varying drug cost, analytic horizon, discount factor, magnitude of LDL-C reduction, and the proportion of statin-intolerant individuals, cost-effectiveness of PCSK9 inhibitor therapy and ezetimibe was highly sensitive only to the cost of the drug and the time horizon (with the lifetime horizon in the base analysis the most optimistic scenario) (eFigure 3 in the Supplement). In probabilistic sensitivity analyses, at 2015 US prices PCSK9 inhibitors were estimated to be cost-effective in 0% of simulations at thresholds of $50 000 per QALY, $100 000 per QALY, and $150 000 per QALY (Figure 1 and eFigure 4 in the Supplement).45,46

Threshold Analyses and Effect on Health Care Spending

A cost-effectiveness threshold of $100 000 per QALY was achieved when the annual price of PCSK9 inhibitors was reduced by 68% to 70% to $4536 (Figure 2 and eTable 11 and eFigure 4 in the Supplement). Simulations that modeled the use of PCSK9 inhibitors instead of ezetimibe among all currently eligible patients resulted in an estimated $592 billion increase in drug spending over 5 years (Table 4 and eTable 12 in the Supplement). Although cardiovascular costs were estimated to decrease by $29 billion over the same period, there was an estimated net increase of $568 billion in health care spending. Adding PCSK9 inhibitor therapy to status quo statin therapy was estimated to generate the greatest net monetary benefit if the willingness-to-pay threshold was at least $423 000 per QALY (eFigure 5 in the Supplement). For willingness-to-pay thresholds ranging from at least $155 000 per QALY to less than $423 000 per QALY, the greatest net monetary benefit was estimated to result from adding ezetimibe to status quo statin therapy. At any level of willingness to pay less than $155 000 per QALY, neither strategy was estimated to yield a net monetary benefit, and the comparator, status quo statin therapy, was projected by the model to be the optimal choice.

Scenario Analyses

Most scenarios resulted in the same or economically less favorable ICERs for PCSK9 inhibitors, including (1) modeling the effects on ASCVD as estimated from drug-specific clinical trials rather than the LDL hypothesis (eTable 13 in the Supplement); (2) incorporating alternative quality-of-life estimates (eTable 14 in the Supplement); (3) stopping incremental therapy at age 75 years (eTable 15 in the Supplement); and (4) modeling a decrement in quality of life related to subcutaneous injections or additional adverse drug reactions (eTables 16 and 17 in the Supplement).

A few scenarios resulted in more economically favorable ICERs or budget projections. Defining the heterozygous FH population using higher LDL-C thresholds resulted in 460 000 fewer adults eligible for PCSK9 inhibitor therapy, a lower ICER ($435 000 per QALY), and a smaller increase in estimated spending ($28.6 billion over 5 years); assuming those with FH have a 2-fold higher ASCVD risk than that predicted by their LDL-C level improved the ICER to $175 000 per QALY. Restricting PCSK9 inhibitor therapy to statin-intolerant patients in the heterozygous FH and ASCVD populations resulted in ICER estimates of $282 000 per QALY and $346 000 per QALY, respectively (eTable 18 in the Supplement). Restricting PCSK9 inhibitor therapy to patients with an incident MI lowered the ICER to an estimated $304 000 per QALY (eTable 19 in the Supplement). Reducing the prevalence of statin intolerance from 10% to 3% resulted in 974 000 fewer individuals eligible for PCSK9 therapy with an estimated decrease in health care spending of $10.2 billion over 5 years. Initiating statin treatment among all individuals with heterozygous FH or ASCVD not currently taking statins resulted in an estimated 214 500 fewer MACE over 5 years, with a net cost savings estimated at $12 billion over 5 years compared with status quo.

Discussion

Quiz Ref IDThis economic evaluation of PCSK9 inhibitors from the US health system perspective demonstrates that their use as indicated could substantially reduce MIs, strokes, and cardiovascular deaths. However, even if they prove highly effective in preventing ASCVD, PCSK9 inhibitors are not cost-effective at 2015 prices, and achieving commonly accepted cost-effectiveness thresholds would require price reductions by more than two-thirds.47 At 2015 prices, PCSK9 inhibitor use in eligible individuals between the ages of 35 and 74 years was estimated to increase annual prescription spending by approximately $125 billion over ezetimibe use (a 38% increase from the approximately $329 billion spent on prescription drugs in 2015) and US health care expenditures by about $120 billion (a 4% increase from the $2.8 trillion dollars in total US health care spending in 2015).48

Quiz Ref IDThe effect of a new medication on health care spending is determined by the size of the target population, duration and effectiveness of therapy, drug price, and costs of care.49 Although new, expensive therapies indicated for short duration or for treatment of rare conditions have thus far been absorbed by the budgets of health systems, the high cost of PCSK9 inhibitors is uniquely challenging. This is because PCSK9 inhibitors are meant to be lifelong therapy not only for the relatively small number of patients with FH but also for a large and growing population with ASCVD. As a result, the potential increase in health care expenditures at current or even moderately discounted prices could be staggering, despite cost savings from averted ASCVD events.

Restricting the population treated with PCSK9 inhibitors is one strategy for containing costs. Higher-risk patient subgroups (such as those with a recent MI or heterozygous FH patients with higher LDL-C levels) would likely derive greater benefit from PCSK9 inhibitors; use in a smaller number of higher-risk patients lowers total spending, but PCSK9 inhibitor therapy is still not cost-effective in these groups at current prices. Quiz Ref IDIdentifying patients with true statin intolerance (by rechallenging patients with statins50 or performing n-of-1 trials to assess statin tolerability51) could also reduce the number of individuals eligible for PCSK9 inhibitors and lower total costs.

The results of multiple scenario analyses suggest that reducing the price of PCSK9 inhibitors remains the primary approach to improving the value of these therapies. Although biologic agents are inherently more expensive to study and manufacture compared with small molecules, these costs may not be the ultimate driver of pricing.52 Furthermore, the US prices of biologic agents have not declined over time and have increased 6% to 12% a year for top-selling rheumatoid arthritis drugs.53 Although generic biosimilars may eventually lower drug costs, their entry has often been delayed by complex manufacturing and approval requirements, extending the effective market exclusivity of the pioneer drugs and reducing price competition after patent expiration.54 Biosimilars of other therapies currently available in the European Union cost 25% to 30% less than the reference biologic agent55; if the US experience with PCSK9 inhibitors is comparable, biosimilar versions of PCSK9 inhibitors would still not be cost-effective. These results are consistent with those of the National Institute for Health and Care Excellence in the United Kingdom: although PCSK9 inhibitors were initially introduced in the United Kingdom at a price less than half that in the United States (Figure 1), they were approved for use in the National Health Service only after manufacturers agreed to an additional price discount.56

Quiz Ref IDIn the face of limited health care resources, payers must consider the potential trade-off between paying for new drug treatments like PCSK9 inhibitors and investing in interventions known to improve access, physician prescription rates, and patient adherence to statin therapy among those at high ASCVD risk. Nationally representative data from NHANES indicate that more than one-third of both FH and ASCVD patients who have an LDL-C level of at least 70 mg/dL are not currently receiving statins, despite evidence of long-term effectiveness, safety, and cost-effectiveness.57 Fully treating these populations that have an indication for statins but are currently not receiving them would actually save an estimated $12 billion over 5 years.

This analysis has several limitations. First, no long-term data on clinical outcomes exist for PCSK9 inhibitors. Although the short-term trials suggest lower rates of MI and cardiovascular death, these were not powered for clinical outcomes, and several nonstatin medications that lower LDL-C have not shown clinical benefit in long-term trials.58 If ongoing clinical trials demonstrate that the drugs do not improve clinical outcomes as predicted by their effect on LDL-C, this model will have overestimated their cost-effectiveness. Second, the effect of PCSK9 inhibitors on total health care spending in the community setting will depend on uptake and adherence, which may vary based on age, educational status, comorbidities, and cost sharing. The long-term effect of missed doses of PCSK9 inhibitor therapy on clinical effectiveness is currently unknown, although from an economic standpoint, patients who stop taking the drug accrue neither costs nor benefits and therefore do not alter the cost-effectiveness of the drug. Third, because LDL-C–lowering treatment in FH may begin in childhood or young adulthood to prevent premature coronary heart disease, the model may not have captured the entire clinical and economic burden of FH or the benefits of LDL-C lowering in childhood or young adulthood. However, there are no data about the efficacy or safety of PCSK9 inhibitors in children and there are limited data in young adults, and PCSK9 inhibitors are currently approved for use only among adults. The base case assumed that the elevated cardiovascular risk among patients with FH is mediated by their high levels of LDL-C along with other known cardiovascular risk factors. Although contemporary data on cardiovascular risk in heterozygous FH are limited, a patient with FH may have higher ASCVD risk than predicted by their LDL-C level, perhaps because of the early-life exposure to high LDL-C. In a sensitivity analysis, doubling ASCVD risk related to LDL-C levels in FH resulted in an improved ICER that was still above the $100 000 per QALY threshold.

Conclusions

Assuming 2015 prices, PCSK9 inhibitor use in patients with heterozygous familial hypercholesterolemia or ASCVD did not meet generally acceptable incremental cost-effectiveness thresholds and was estimated to increase US health care costs substantially. Reducing annual drug prices from more than $14 000 to $4536 would be necessary to meet a $100 000 per QALY threshold.

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Article Information

Corresponding Author: Kirsten Bibbins-Domingo, PhD, MD, MAS, University of California, San Francisco, Division of General Internal Medicine, Zuckerberg San Francisco General Hospital, PO Box 1364, San Francisco, CA 94143-1364 (kirsten.bibbins-domingo@ucsf.edu).

Author Contributions: Drs Kazi and Bibbins-Domingo had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kazi, Moran, Ollendorf, Pearson, Tice, Bibbins-Domingo.

Acquisition, analysis, or interpretation of data: Kazi, Moran, Coxson, Penko, Ollendorf, Tice, Guzman, Bibbins-Domingo.

Drafting of the manuscript: Kazi, Penko, Bibbins-Domingo.

Critical revision of the manuscript for important intellectual content: Kazi, Moran, Coxson, Ollendorf, Pearson, Tice, Guzman, Bibbins-Domingo.

Statistical analysis: Kazi, Moran, Tice, Guzman, Bibbins-Domingo.

Obtaining funding: Ollendorf, Bibbins-Domingo.

Administrative, technical, or material support: Kazi, Penko, Ollendorf, Tice.

Study supervision: Kazi, Moran, Pearson, Bibbins-Domingo.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Ollendorf and Pearson are employees of the Institute for Clinical and Economic Review, an independent organization that evaluates the evidence on the value of health care interventions, which is funded by grants from the Laura and John Arnold Foundation, Blue Shield of California Foundation, and the California Healthcare Foundation. The organization’s annual summit is supported by dues from Aetna, America’s Health Insurance Plans, Anthem, Blue Shield of California, CVS Caremark, Express Scripts, Harvard Pilgrim Health Care, Omeda Rx, United Healthcare, Kaiser Permanente, Premera Blue Cross, AstraZeneca, Genentech, GlaxoSmithKline, Johnson & Johnson, Merck, National Pharmaceutical Council, Takeda, Pfizer, Novartis, Eli Lilly, and Humana. Dr Tice reports receiving grant funding from the Institute for Clinical and Economic Review. No other disclosures are reported.

Funding/Support: Portions of this work were presented to the New England Comparative Effectiveness Public Advisory Council, a program of the Institute for Clinical and Economic Review that is supported by grants from the New England States Consortium Systems Organization and the Laura and John Arnold Foundation.

Role of the Funder/Sponsor: Funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Disclaimers: Dr Bibbins-Domingo is the chair of the US Preventive Services Task Force (USPSTF). This article is the original work of its authors and does not represent the position or recommendation of the USPSTF. The Framingham Cohort and Framingham Offspring Research Materials were obtained from the US National Heart, Lung, and Blood Institute (NHLBI) Biologic Specimen and Data Repository Information Coordinating Center. The manuscript does not necessarily reflect the opinions or views of the Framingham Cohort, Framingham Offspring, or NHLBI.

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